This was a presentation at FOGSI workshp on RPL at Chandrapur on alloimmune factors Dr Rajesh Gajbhiye

1. FOGSI Workshop
Preventing Early Pregnancy Loss (EPL)
The Cocktail Therapy
Dr. Suchitra Pandit Dr. Ritu Joshi Dr. Shailesh Kore Dr. Kedar Ganla
President Vice -President Chairperson National Coordinator
Workshop supported by Unconditional Educational Grant by

2. Alloimmune Background in
Early Pregnancy Loss (EPL)
Dr Rajesh Gajbhiye
Nagpur

3. Introduction
• About 50% of pregnancies are lost after
conception
• About 15 % are lost after clinically detectable
pregnancies
• Causes are not known in more than 50% of
cases of RPL
• Such large unexplained causes has fuelled
interest in immunological causes.

4. Pregnancy is a semi-graft
50% of the antigens
are foreign

5. Immunomodulation
during pregnancy
Embryo / Fetal antigens produce two types of antibodies:
• T Helper I Cell response
• T Helper II Cell response

6. Immune reaction during
pregnancy
Fetus with
Paternal
antigens
T helper 1
cell response
Abortion of
The Fetus
T helper 2
cell response
Protection of
The Fetus

7. Embryo / Fetus
T helper 1 cell response activated
Tumor Necrosis Factor ά
Interleukin2
Natural killer Cells
Lymphokine Activated Killer Cells
Abortion of Fetus
Cascade
Reaction

8. What are Cytokines ?
Secreted molecules that regulate the intensity and duration of
the immune response by exerting a variety of effects on
lymphocytes and other immune cells
Cytokines are the messengers of the Immune System
(Th1 : TNFα, Il-2, Th2 : IL-4, IL-10)
just as
Hormones are the messengers of the Endocrine System

9. Cytokines and TNF- b
 Th-1 cytokines trigger thrombotic / inflammatory processes
at the maternal uteroplacental blood vessels by activation
of vascular endothelial cell procoagulant.
 Th-2 cytokine inhibit Th-1 induced tissue destruction by
monocytes.
 TNF-b is supposed to suppress the growth of trophoblasts
by inducing apoptotic changes in these cells.

10. Role of Interleukin in the
Luteal Phase
 Luteal phase of young healthy women is associated with
decline in Interleukin 2 levels
Hormone Metab. Res. 2001: 33; 348-53.
 Luteal phase in healthy non pregnant women
 Decrease in IL-2 blood levels.
 Decrease in intracellular IL-2 containing lymphocytes.
 Seen as a start of immune suppression necessary for
embryo nidation.
 Could also be the cause of premenstrual infections seen
in young women.

11. Embryo protective
Immunomodulation
- How is this brought about?
Normal Pregnancy
Progesterone(P) Receptor Activation
Progesterone Induced Blocking Factor(PIBF)
Blocks Cascade Reaction, Shift to Th type 2
Embryo Protective Immunomodulation
Protection of Embryo / Fetus

12. Embryo Protective
Immunomodulation – What is it?
3 Positive responses
T helper 2 cell response NK Activity
Asymmetric Antibodies
No binding with Antigen
No activation of Complement
Cascade
Protection of Fetus
Protective
Cytokines
IL 3
IL 4
IL 5
IL 6
IL 10
IL 13
Raghupathy et al., (2000): Cytokine production by maternal lymphocytes during normal human pregnancy and in
unexplained recurrent spontaneous abortion. Hum. Reprod. 15(3); 713-18.

13. Progesterone-induced Blocking
Factor (PIBF) Link between the
Endocrine and Immune System
Progesterone
PIBF
Th2
Normally
Progressing
Pregnancy
Progesterone
PIBF
Th1 Miscarriage
Ru 486
Progesterone
PIBF
+anti-PIBF
Th1 Miscarriage
Szekeres - Bartho J et al. Int Immunopharm 2001; 1:1037-1048.

14. Increased Th1 Cytokine Response in Women
with RSA Losses & with Multiple Implantation
Failures after IVF
Comparison of Th1/Th2 cytokine producing CD3+/CD8– (T
Control, n = 21
RSA, n = 26
IVF failure, no Hx SA, n = 14
helper) cell ratios
** p < 0.01
* p < 0.05
**
*
Kwak -Kim JY et al. Hum Reprod. 2003 Apr;18(4):767-73.
70
60
50
40
30
20
10
0
*
**
*
IFNγ / IL-4 IFNγ / IL-10 TNFα / IL-4 TNFα / IL-10

15. 160
140
120
100
80
60
40
20
7-19 20-29 30-37 38-41
Weeks of gestation
PIBF concentration (ng/ml)
Normal pregnancy
Miscarriage /
Preterm labour
<41 L
PIBF Concentrations in
Normal and High Risk
Pregnancies
* p<0.05
Polgar B et al. Biol Reprod 2004; 71:1699-1705.
*
*
*

16. P-receptors in Pregnancy
Lymphocytes
Activation
γ/δ
PR+
P
P
P
P
PIBF
+
Normally
Progressing
Pregnancy
Th2 / Th1
+
Szekeres-Bartho J et al. Int Immunopharm 2001; 1:10371-1048.
γ/δ
 Natural Killer
Cell Activity

17. Decidual NK cells
• Decidual NK Cells appear to be mainly
involved in alloimmune abortion.
• Under influence of Th1 cytokines they damage
the trophoblasts.
• Patients who abort have increased NK cell
activity and NK cells of CD3,CD 56,CD 16
types.

19. Immunomodulation
during pregnancy
 Molecules like dydrogesterone inhibit the cytokines through
PIBF, thereby enhancing chances of successful pregnancy.
(Rajraghupati – Abstract World Congress. Hong Kong, Dec 2-5, 2001).
 No other progesterone has so far been experimented on this
aspect of immunomodulation

20. IMMUNOLOGIC FACTORS
Autoimmune Alloimmune
(directed to self) (directed to foreign
tissues/cells)
-Systemic Lupus Erythmatosus An abnormalmaternal
-Antiphospholipid Syndrome immune response to
fetal or placental antigen.

21. Autoimmune
• Systemic Lupus Erythmatosus (SLE)
-Risk for loss is 20%,mostly in 2nd and 3rd
trimester of pregnancy and associated with
antiphospholipid antibodies.
• Antiphospholipid syndrome (APA)
– 5 - 15 % of womenwith RPL may have APA
APA likely induce microthrombi at placentation site.
Altered vascularity affects developing embryo,
induces abortion

22. Antiphospholipid syndrome
– An Autoimmune disorder having specific clinical & lab
criteria. --Sapporo criteria
Diagnosis requires at least one of each.
CLINICAL 1) Thrombolic events-arterial,venous,small
vessel
2)Pregnancy loss- ≥3 losses at <10wks
gestation, fetal death after 10wks,premature birth at
<34wks associated with severe preeclampsia or
placental insufficiency.
LABORATORY 1) Lupus Anticoagulant
2) Anticardiolipin antibodies(IgG or IgM)
Any lab test results must be observed on at least 2 separate
occasions 6 wks apart.

23. • Recent metaanalysis shows that the
combination of Aspirin + Heparin is better
than Aspirin alone in achieving live births
in women with recurrent pregnancy loss
and antiphospholipid antibodies
Mak A et al, Rheumatology (Oxford) 2010
23
Aspirin alone v/s Aspirin + Heparin

24. • There is controversy as to whether LMW
Heparin is effective in preventing
recurrent pregnancy loss
• Consider costs, convenience and
compliance before initiating therapy
• Therapy should be started when fetal
cardiac activity is demonstrated and
continued throughout pregnancy and
postpartum
• Heparin in prophylactic doses needs to
be stopped for about 24 hours around
the time of labor and delivery
24

25. • Heparin in prophylactic doses NEED not
be monitored and does not require
monitoring by coagulation parameters
• Standard doses
– Unfractionated heparin – 5000 units sc bd
– Enoxaparin – 40 mg sc daily or in two doses
25

26. • Meta analysis
• Heparin with Aspirin imroved live birth
• 25-75%
• In 20-30% loss ,inspite of therapy
• Alt treatment glucocoticids or IVIG
• IVIG is no more effective than aspirin and
Heparin in pts of APS

27. Alloimmune mechanism
Normally pregnancy(foreign tissue graft) is
tolerated by the maternal immune system through
formation of antigen blocking antibodies.
Felt that in couples that share similar types of HLA,
there is inadequate formation of blocking
antibodies in the maternal environment.
Therefore the maternal immune system mounts an
immune response to the implanting pregnancy and
a spontaneous abortion occurs.

28. Alloimmune mechanism
Although previous studies have concluded that
there was a higher degree of HLA sharing in
couples with recurrent abortion, multiple
recent studies have not confirmed this.
Multiple investigators have attempted to modulate
the immune response using
1) paternal WBC immunization
2) IV Immunoglobulin
3) donor seminal plasma vaginal
suppositories

29. ALLOIMMUNITY DIAGNOSIS
HLA Typing-HLA sharing-Insufficient
antigenic stimulus
• Antipaternal antibodies- absence
maternal unreponsiveness
• Husband’s lymphocytes + wife’s serum
to find antibodies
None of the above test Diagnostic

30. • In practice study of Peripheral blood NK cells
is used.
• NK cell markers -Immunotherapy

31. Immunologic Factors
-Treatment
• Immunostimulating Therapies-Leukocyte
Immunization
• Immunosuppressive Therapies

32. Immunostimulating Therapies-
Leukocyte Immunization
– stimulation of the maternal immune system using
alloantigens on either paternal or pooled donor
leukocytes
– a number of reports support possible mechanism for
potential therapeutic value
– however, there is no credible clinical or laboratory
method to identify a specific individual who may
benefit from such therapy
– leukocyte immunization also poses significant risk to
both the mother and her fetus
• graft-versus-host disease, severe intrauterine growth
retardation, and autoimmune and isoimmune complications

33. TREATMENT
Acive immunisation-Transfusion of
husband’s lymphocytes
Pure suspension of husband’s
lymphocytes
[ 300ml of blood = 10ml of suspension ]
Inject 5ml IV, 1 ml subcu and 1ml
intradermal

34. • Effective presentation of paternally derived
antigen and regulate maternal response
through suppression of NK cell activity
• Increases Th2 type immune response
• Cochrane review 2006 doesnot support this
therapy.
• ASRM it has higher side effects and marginal
benefits

35. Intravenous immunoglobulin
Passive immuisation
• Mechanism
– Blockage of allogenic cytotoxic reactions
– Suppresses NK cell activity
• disadvantage
– expensive, invasive, and time-consuming, requiring
multiple intravenous infusions over the course of
pregnancy
• side effects
– nausea, headache, myalgias, hypotension, anaphylaxis

36. • 0.5 g/Kg body weight IVIG started at 5 wks
• Followed by 0.35g/kg every 3 weeks until 24
weeks.
• Only therapeutic solution increased activity of
NK Cells
• When used as homogenous group not
effective in various meta-analysis but in
properly selected pts beneficial.

37. FUTURE
• Cytokines GM-CSF9Granulocyte macrophage
colony stimulating Factor)
• TGF-b

38. • In addition to immunotherapy hormonal
support (Progesterone and HCG) has been
used to improve the live birth rate in
recurrent abortion by modulating balance
between Th1 and Th2 cytokines.

39. Progesterone
• Mechanism
– inhibits Th1 immunity
– shift from Th1-to Th2 type responses
• administered
– intramuscularly
– intravaginally
• may increase local, intrauterine concentration
• averting any adverse systemic side effects

40.  Progesterone favours the development of human T helper
cells producing Th2-type cytokines and promotes IL – 4
production.
Piccinni MP, Gindizi MG et.al , J. Immunal 1995; 155 : 128-133
 Progesterone inhibits in vitro embryotoxic Th1 cytokine
production in trophoblast in women with recurrent
pregnancy loss
 Choi BC, Polgar K et. Al Hum. Reprod 2000; 15 (supp 1) 46-
59
Hormonal
Immunomodulation
Progesterone

41. Hormonal
Immunomodulation
Modulation of cytokine production by dydrogesterone in
lymphocytes from women with recurrent miscarriage.
Dydrogesterone inhibits the production of the Th1 cytokines IFN-
γ and TNF–α from lymphocytes and up-regulates the production
of the Th2 cytokines IL-4 & IL-6 inducing Th1 to Th2 cytokine shift.
Raj Raghupathy et. al BJOG 112; 1 – 6 2005

42. Progestogens in
Implantation in ART Cycles
• LPD & implantation failure results from
abnormal serum E2:P ratio or abnormal
E2:P receptor ratios
• Mitigate the deleterious effects of hyper
estrogenism on endometrial
development

43. Effective Luteal Phase
Means:
• Effective secretory endometrial
preparation “Firm” implantation
• Effective endometrial
immunomodulation to prevent
embryonic rejection

44. Effective Luteal phase
Both these immunophysiological functions are carried out
primarily by Progesterone backed up by estrogen.
 Estrogen induces nuclear progesterone receptors
 Progesterone then acting through its own receptor produces a
mediator protein known as progesterone induced blocking
factor (PIBF).

45. Luteal phase defect (LPD)
• LPD is the failure of the uterine lining to be in the right
phase at the right time
• May be due to inadequate
progesterone production by
corpus luteum
• Or inadequate response of
endometrium to the normally
circulating level of progesterone.

46. Incidence of LPD:
 26.5% in infertile women
(Sahmay et al; Fert. Menopausal Stud. 1995;40
(6) : 316-321).
 45% in patient suffering from
recurrent miscarriage
(Daya et al; Am.J. Obst. Gyn. 1988;158 : 225-
232).

47. Cause of LPD in Non ART
cycles
 Poor follicular phase inadequate Luteal phase.
 Premature LH Stimulation of immature
granulose cells.
 Abnormal patterns of
LH secretion in the
Attenuated “LH” &
Luteal phase
“FSH” ovulatory surge
 Decreased endometrial nuclear progesterone receptors
 Can also be found with normal levels of progesterone

48. Causes of LPD in ART
cycles
• CC INDUCTION
Antiesterogenic to endometrium
Reduced endometrial progesterone
receptor production
• ART
 Long downregulation resulting in LPD (Smitz, Devroey 1988)
 Use of Antagonist
 Supraphysiological level of E2 – Leutolytic
 Multiple puncture of follicles – damage to
granulosa cells.

49. • Diagnosis
• Sreum progesterone level less than
10ng/ml in midluteal phase.
• 3 estimation between day 5-8 should be
30ng/ml.
• Out of phase endometrium
– Histological lags 2days behind menstrual
datesNot used now a days

50. • USG Doppler
• CL high resistence flow
• Ovarian RI is similar in both ovaries
Newer tests
PIBF measurements

51. Treatment for LPD
Progesterone supplementation
given in suspected cases or empirically
Prevents 33% miscarriages
Reduces 28% to 6% along with follicular
maturing drugs
• HCG supplementation-majority have PCOS
and LPD

52. Progestogens for Luteal
phase support in ART cycles
• Needs to be given daily basis either oral,
vaginal, IM routes
• Neutralize the negative effects of hyper
estrogenism on endometrial
development
• Immunosuppressive effect facilitating
implantation (Immunomodulation)

53. HCG for Luteal phase
support in ART cycles
• Frequent dosing intervals of 3 - 4
days
• Increases incidence of OHSS
• HCG increases Luteal E2 to
undesirable levels, upsetting E2 : P
ratio

54. • HCG is good for luteal support
• Natural micronised progesterone is drug of
choice for LPD
• Vaginal route is preferred over others.

55. • Chochrane review –IVIG is ineffective
• In poor prognosis patients in whom other
treatments have failed and in properly
selected patients IVIG has been found to
improve birth rate.
• If immunotherapy fails and embryo is
karyotypically normal then Surrogacy is
advised.

56. • Many questions to be answered
• Many stages of maternal immune response
remain unclarified
• Available diagnostic methods can only provide
indirect marker
• Results must be interpreted with caution
• Appropriate immnointervention be
admisnistered.

57. Acknowledgement
Thanks to YOU - For being wonderful audience
EPL Team - who conceptualized and created this program -
Team Lead by
• Dr . Suchitra N. Pandit - President FOGSI
• Dr. Ritu Joshi - Vice President FOGSI
• Dr. Shailesh Kore - Chairperson Genetic & Fetal Medicine
-
Committee, FOGSI
• Contributors - Dr . Nozer Sheriar, Dr. Kedar Ganla, Dr. Ameet Patki,
Dr. Sarita Bhalerao, Dr. Parikshit Tank, Dr. Bhaskar Pal,
Dr. Bharti Dhorepatil, Dr. Atul Ganatra, Dr. Kalyani Ingle
Dr. Ameya Purandare, Dr. Kundan Ingle, and all the
Doctor Speakers.
For supporting the program with unconditional
educational grant
For organizing and managing the program across
the country

58. Thankyou

59. Outline
• Basic facts
• Levels
• Treatment of low progesterone levels
• Role of progesterone in pregnancy
• Role of progesterone in ART
• Conclusion

60. Basic facts:
 Progesterone support in pregnancy has been in use
for nearly 60 years, dating back to the 1940s.
 Its initial use was in patients who had habitual
spontaneous abortion caused by Luteal phase
deficiency (LPD).This is due to a failure of the
function of the corpus luteum in the production of
progesterone ,which is indispensable during the first
seven weeks of pregnancy.

61. Symmetric Antibodies
Exact alignment between binding surfaces of the paternal
antigens and maternal antibodies causes activation of the
complement cascade
Abortion of the fetus
Von Wolff et al., (2000): Regulated expression of cytokines in human endometrium throughout the menstrual
cycle: dysregulation in habitual abortion. Mol. Hum. Reprod. 6; 626-34.

62. Basic facts:
 Surgical removal of the corpus luteum during this
period of time results in pregnancy loss and
progesterone replacement can help maintain the
pregnancy.
 There is evidence of support in the concept that
progesterone given in early pregnancy may be useful
in some women with recurrent miscarriage and that
the measurement of serum progesterone levels in
early pregnancy can be an adjunctive marker for the
further assessment of pathologic pregnancies.

63. Levels
 Progesterone levels are based on her menstrual
cycle and in the stage of pregnancy.
 Before Pregnancy
Prior to ovulation: Progesterone levels tend to be
< 2 ng/ml
After Ovulation: > 5 ng/ml
 In Pregnancy
Progesterone levels rise with pregnancy. This can
often indicate the health of a pregnancy.
First Trimester: 9-47 ng/ml
Second Trimester: 17-147 ng/ml
Third Trimester: 55-200 ng/ml

64. Progesterone in the Luteal
Phase and Pregnancy
Progesterone
HCG
FSH
LH
2 4 6 8 10 12 14 16 18 20
Days
4 6 8 10 12 14
Weeks
Menses Ovulation Implantation
Speroff L et al. Clinical Gyn Endo and Infert 1999; 6: 235.

65. Progesterone levels in
Pregnancy

66. Maintenance of Early
Pregnancy
Syncytiotrophoblast
Cytotrophoblast
Yolk sac
Amnioti
c
cavity
Chorionic
cavity
hCG
Lacunar
network
Progesterone
Regulation of
prostaglandin
production
VDGF-VEGF
receptors
Angiogenesis
Progesterone
Blood
vessels
Endometrial
gland
Decidualized
endometrial stroma
Chorion
Maternal blood
sinusoid
Facilitation
of immune
tolerance
Suppressor
macrophage
Corpus luteum
of ovary
Decreased
complement
activity
Altered antigen
presenttaion
(HLA-G)
Regulation of
leukocyte traffic by
cytokines and chemokines
Indoleamine
2,3-dioxygenase
Norwitz et al., N Engl J Med. 2001; 345(19):1400-8.

67. Classification of Progestogens
Schindler AE et al. Maturitas 2003; 46SI:S7-S16.
Natural
Found in nature
Synthetic
Structurally related to
progesterone or
testosterone
17a-
hydroxyprogesterone
19-nortestosterone
•Medroxyprogesteron
e
acetate (MPA)
• Megestrol acetate
• Cyproterone acetate
GONANES
• Norgestrel
•Norgestimate
•Gestodene
19-norprogesterone
• Trimegestone
ESTRANES
• Norethisterone =
Norethindrone
acetate (NETA)
• Allylestrenol
• Progesterone
SSTTEERROOIIDDSS
Retro progesterone
Dydrogesterone

68. Biological Activities of the
Progestogens
Progestogen Progestogenic Estrogenic Androgenic Glucocorticoid
Dydrogesterone + − − −
Progesterone + − − +
Cyproterone
+ − − +
acetate
MPA + − ± +
Norethisterone + + + −
Schindler AE et al. Maturitas 2003; 46SI:S7-S16.

69. Progesterone and Fetal
Brain development
• Brain is sensitive to progesterone during critical periods of
development and maturation
• Dramatic sex differences in progesterone receptor (PR)
expression, in which males express higher levels of PR than
females in specific regions, suggest PR may play an
important role in the sexual differentiation of brain and
behavior.
Wagner CK, Endocrinology 2008 June;149(6):2743-9

70. Re Genesis – Pilot Study
(Phase I) 2002-04
 315 ICSI and 94 recipients on donor oocyte program were included in
the trial. 89 patients were at risk of OHSS (E2 > 2000 pg/ml)
 All were matched for Demographic factors including age, social status,
infertility factors and years of infertility.
 All patients underwent
 long term down regulation with GnRHa for a minimum of 10 days.
 Controlled ovarian stimulation with Gonadotropins
 Recipients on the donor oocyte program were started on Tab.
Progynova (estradiol valerate) in an increasing dose from day of
stimulation of the Donor.

71. Re Genesis – Pilot Study
(Phase I) 2002-04
 Patients on any other protocol were excluded from the study.
 All patients received 600 mg of micronized progesterone
(utrogestan) vaginally from day of oocyte retrieval.
 In addition, patients were randomized to either receive
Dydrogesterone 20 mg or placebo daily from the day of
embryo transfer till serum b hCG which if more than 50 mIU/
ml, the treatment was continued.
 A USG was done to confirm a viable pregnancy after 3 weeks.
 Only intrauterine viable pregnancies were considered as
positive for pregnancy.

72. Results: I
ICSI Patients: 315
Treatment with Dydrogesterone 112 (35.5%)
Treatment with no Dydrogesterone 203 (64.4%)
Pregnancy Rate
With Dydrogesterone 37 (33.03%)
With no Dydrogesterone 48 (23.64%)
P value NS

73. Results: II
Patients at risk of OHSS : 89
Treatment with Dydrogesterone 57 (64.04%)
Treatment with no
32 (35.95%)
Dydrogesterone
Pregnancy Rate
With Dydrogesterone 21 (36.84%)
With no Dydrogesterone 09 (28.12%)
P value NS

74. Results: III
Recipient on Donor Oocyte Program : 94
Treatment with Dydrogesterone 49 (52.12%)
Treatment with no Dydrogesterone 45 (47.87%)
Pregnancy Rate
With Dydrogesterone 21 (42.85%)
With no Dydrogesterone 07 (15.55%)
P < 0.001
Chi. Square test

75. Re Genesis – (Phase II) 2004-06
 450 ICSI and 120 recipients on donor oocyte program were included
in the trial. 105 patients were at risk of OHSS (E2 > 2000 pg/ml)
 All were matched for Demographic factors including age, social
status, infertility factors and years of infertility.
 All patients underwent
 long term down regulation with GnRHa for a minimum of 10
days.
 Controlled ovarian stimulation with Gonadotropins
 Recipients on the donor oocyte program were started on Tab.
Progynova (estradiol valerate) in an increasing dose from day of
stimulation of the Donor.

76. Re Genesis – (Phase II)
 Patients on any other protocol were excluded from the study.
 Patients were randomized to either receive 600 mg daily of
micronized progesterone (utrogestan) vaginally or
Dydrogesterone 30 mg daily from day of oocyte retrieval.
 Serum b hCG was tested 14 days from embryo transfer and if
more than 50 mIU/ ml, the treatment was continued.
 A USG was done to confirm a viable pregnancy after 3 weeks.
 Only intrauterine viable pregnancies were considered as positive
for pregnancy.
2004- 05

77. Results - I
ICSI : 450 Patients
Treatment with Dydrogesterone 248 pts [55.1%]
Treatment with Micronised
202 pts [44.9%]
Progesterone
Pregnancy Rate
With Dydrogesterone 97 [*39.1%]
With Micronised 54 [26.7%]
• By Chi Square Test * P<0.01 Significant

78. Results - II
At risk of OHSS – 105 Patients
Treatment with Dydrogesterone 60 [57.13%]
Treatment with Micronised
45 [42.8%]
Progesterone
Pregnancy Rate
With Dydrogesterone 25 [*41.6%]
With Micronised Progesterone 16 [35.5%]
• By Chi Square Test * P<0.01 Significant

79. Results - III
Donor oocyte program – 120 Patients
Treatment with Dydrogesterone 58 [48.3%]
Treatment with Micronised
62 [51.6%]
Progesterone
Pregnancy Rate
With Dydrogesterone 28 [*48.2%]
With Micronised Progesterone 21 [33.8%]
• By Chi Square Test * P<0.001 Significant

80. Paper presented at …
• Five National conferences in India
• Teaching Universities in China Egypt and Vietnam
This paper is published in Gynecological Endocrinology, October 2007; 2(S1): 68-72

81. Functions of progesterone
 Converts the endometrium to its secretory shape to prepare uterus
for implantation.
 Affects the vaginal epithelium and cervical mucus , making it thick to
un-penetrable sperm.
 During implantation & pregnancy ,progesterone appears to decrease
the maternal immune response to allow for acceptance of pregnancy.
 Decreases contractility of uterine smooth muscle.
 Inhibits lactation during pregnancy. Fall in the levels following
delivery is one of the triggers for milk production.
 Drop in progesterone is possibly one step that facilitates the onset of
labor.

83. Treatment for low
progesterone levels
Low progesterone levels are associated with increased risk of
miscarriage in the first trimester. There are many forms of
treatment or supplementation that help to increase and maintain
the production of progesterone. The treatment options listed
below are generally followed for the first trimester of pregnancy.
Dosages vary based on specific need or deficiency.
Intra-muscular progesterone injections- self administered for the
first trimester of pregnancy
Oral progesterone capsules (standard or sustained release)
progesterone vaginal pressaries
HCG- Human chorionic gonadotropin

84. Routes of administration
• Intramuscular (painful, low patient compliance)
• Vaginal (very effective, available as pessaries, gel,
effervescent tablets)
• Oral (Micronised progesterone not effective due to
the hepatic first bypass )

85. Implantation
 Shedding of the zona pellucida
 Orientation
 Apposition
 Attachment
 Adhesion

86. Role of Progestins in the
Treatment of Threatened
and Habitual Abortion
Spontaneous abortion occurs in
approximately 15% of all clinically
recognized pregnancies but up to
45% after 3 consecutive miscarriages
Speroff L et al. Clinical Gyn Endo and Infert 1999; 6:1043-1044.

87. Progestogens for
preventing miscarriage
No evidence for routine use
However in women with recurrent miscarriages of
3 or more , statistically significant decrease rate in
miscarriage compared to placebo or no treatment.
No statistical difference between route of
administration (oral, IM, vaginal)
Cochrane Database Reviews 2008 Issue 2 Haas DM, Ramsay PS

88. Adverse effects
 Cramps, abdominal pain, skeletal pain, headaches
 Diarrhoea, nausea, vomiting
 Breast enlargement, joint pains
 Thirst, increased appetite, drowsiness, excessive urination at
night.
 Mood swings, emotional instability, abnormal crying, insomnia,
sleep disorders.
 Plays an important role in the signaling of insulin release &
pancreatic function, affect susceptibility to diabetes.
 Women with high levels of progesterone during pregnancy are
likely to develop abnormalities

89. Immunomodulation
during pregnancy
If T helper I cell response is activated it produces harmful
cytokines and fetus is rejected.

90. Interferon's and progesterone
for establishment and
maintenance of pregnancy, interactions
among novel cell signaling pathways
 Interferon's (IFNs) Type I and /or Type II are important in
establishing uterine receptitivity to implantation in mammals.
 Uterine receptivity to implantation is progesterone
dependent. Hence IFNs and progesterone activate
complimentary cell signaling pathways to modulate
expression of genes for attachment of trophectoderm to
uterine luminal and superficial glandular epithelia .
Repmed Biol 2008 Nov:8 (3);179-211

91. Luteal Phase Support in
Assisted Reproduction Cycles
(Cochrane Review)
• Selection Criteria for Review : 59 randomized controlled trials
of luteal phase support after ART treatment
• Objectives /Conclusions
1) Does luteal phase support after assisted reproduction increases the
pregnancy rate?
- Yes
(2) What is the optimal hormone for luteal phase support?
- hCG does not provide better results than progesterone and is
associated with a greater risk of OHSS when used with GnRHa
(3) What is the optimal route of progesterone administration?
- This has not yet been established
Daya S, Gunby J. Cochrane Review 2004; Issue 3.

92. • Natural miracle known as immunological
paradox of pregnancy.

93. APAS
• Treatment
1. Low Molecular weight Heparin
– 3000 IU subcut twice a day
– Expensive treatment
1. Un-fractionated Heparin is better option
2. Low dose Aspirin
3. Steroids? Mainly for anti nuclear antibodies
– 10 – 20 mg prednisolone / day

94. Immunosuppressive
Therapies
– To antiphospholipid antibodies and to
inappropriate cellular immunity toward the
implanting fetus
• intravenous immunoglobulin
• progesterone